To elucidate the pathogenesis of Parkinson' s disease and to develop a new therapy for the disease

Parkin和PINK1揭示了泛素化和线粒体完整性是疾病发病的关键因素。在这项研究中，我们发现PINK1在稳态条件下以线粒体膜电位依赖的方式快速和组成性地降解，并且线粒体膜电位的损失稳定了PINK1的线粒体积累。此外，PINK1将Parkin从细胞质中招募到低膜电位的线粒体，启动受损线粒体的自噬降解。此外，我们还利用来自parkin KO小鼠的β细胞分析了胰岛素分泌系统。我们发现胰岛素分泌系统的第一阶段选择性损伤。这一发现可用于阐明神经元细胞死亡的发病机制。此外，我们分析了野生型和突变型ATP13A2的细胞定位变化，ATP13A2是Park9的致病基因。野生型定位于溶酶体的外膜。相反，突变体位于内质网。定位的差异会引起功能缺失效应。

Parkin and PINK1 has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. In addition, we analyzed the secretion system of insulin using beta-cells originated from parkin KO mice. We identified selective impairments of phase I of insulin secretion system. This finding could be available for elucidating the pathogenesis of neuronal cell death. Moreover, we analyzed the alteration of cellular localization of both wild and mutant types of ATP13A2 that is a causative gene for Park9. The wild type localized on the outer membrane of lysosome. In contrast, the mutants located in the endoplasmic reticulum. The difference of localization could induce the loss-of-function effects.